To assess whether the observed numbers and seasonality of deaths in Australia during 2020 differed from expected trends based on 2015–19 data.We used provisional death data from the Australian Bureau of Statistics, stratified by state, age, sex and cause of death. We compared 2020 deaths with 2015-19 deaths using interrupted time series adjusted for time trend and seasonality. We measured the following outcomes along with 95% confidence intervals: observed/expected deaths (rate ratio: RR), change in seasonal variation in mortality (amplitude ratio: AR) and change in week of peak seasonal mortality (phase difference: PD).Overall 4% fewer deaths from all causes were registered in Australia than expected in 2020 [RR 0·96 (0·95-0·98)] with reductions across states, ages and sex strata. There were fewer deaths from respiratory illness [RR 0·79 (0·76-0·83)] and dementia [RR 0·95 (0·93-0·98)] but more from diabetes [RR 1·08 (1·04-1·13)]. Seasonal variation was reduced for deaths overall [AR 0·94 (0·92-0·95)], and for deaths due to respiratory illnesses [AR 0·78 (0·74-0·83)], dementia [AR 0.92 (0.89-0.95)] and ischaemic heart disease [0.95 (0.90-0.97)].The observed reductions in respiratory and dementia deaths and the reduced seasonality in ischaemic heart disease deaths may reflect reductions in circulating respiratory (non-SARS-CoV-2) pathogens resulting from the public health measures taken in 2020. The observed increase in diabetes deaths is unexplained and merits further study. Key MessagesWe undertook an interrupted time series analysis of the number and seasonality of deaths in Australia during 2020 compared with 2015--19.We found 4% fewer deaths from all causes during 2020 in Australia than expected, driven by reductions in respiratory and dementia deaths in older age groups.There was also reduced seasonality in ischaemic heart disease deaths, and no changes in cerebrovascular or cancer deaths. More Australians died from diabetes than expected in 2020.Public health measures adopted in 2020 were associated with incidental mortality reductions in a number of non- COVID diseases. Retaining some of the adopted behavioural changes in the post-pandemic era merits careful consideration.,,There were increased deaths in 2020 associated with the COVID-19 pandemic in many countries, including Germany, France, Italy, Switzerland, Portugal, Sweden, Russia, Brazil, Peru, Israel, Japan, the UK, the USA and Europe as a whole.In contrast to the above, mortality rates have tended not to increase in countries where there was successful suppression (and often temporary elimination) of SARS-CoV-2 infection. For example, New ZealandThe overall objective of this study was to assess the potential impacts of the Australian pandemic response on non-COVID-19 disease mortality. Our primary aim was to compare the expected with the observed number of deaths in Australia in 2020 using available provisional mortality data, stratified by cause of death as well as by state, age and sex. Our secondary aim was to explore a hypothesis that in addition to a change in the total number of deaths, the timing of deaths throughout the year  may have changed. Assessment of the seasonal pattern may allow detection of more subtle changes in mortality during 2020. The nature of some seasonality measures as ratios (see Methods below) means that these outcomes are less confounded by the possibility of incomplete reporting of deaths in 2020. Moreover, changes in seasonal pattern can provide some evidence that any observed reductions are related to a reduction in factors that drive the seasonality of disease, such as reductions in circulating respiratory viruses.Data for this study were sourced from a publicly available dataset maintained by the Australian Bureau of Statistics (ABS).Data were available as weekly totals of deaths, grouped by the date on which the death occurred. Week 1 of a given year begins on 1 January, and each of Weeks 1-52 contain 7 days. Week 53 contains 1 day (31 December) or 2 days during leap years. Published causes of death were grouped according to the International Classification of Diseases (ICD-10) and are limited to: COVID-19 (U07), ischaemic heart disease (I20-25), cerebrovascular disease (I60-69), respiratory disease (J00-J99), chronic lower respiratory disease (J40-47), influenza (J09-J11), pneumonia (J12-18), cancer , diabetes (E10-14), dementia .P-value was <0.05. We verified the chosen models by checking the autocorrelation and partial autocorrelation of residuals. Analyses were performed in R 3.6.3.We assessed for changes in mortality in 2020 in each of the above categories  using interrupted time seriesChange in mortality in 2020 was assessed by the ratio of observed deaths to expected deaths. The observed number of deaths refers to the total number of doctor-certified deaths that took place in Weeks 1-52 of 2020. To calculate the expected  number of deaths, we forecast the number of deaths in 2020 using the selected model but with the effect of 2020 set to zero. We calculated the ratio of observed to expected deaths and produced confidence intervals using 95% confidence limits of our counterfactual projections. IJE online, for more details]. The amplitude was defined to be the maximum contribution of the seasonal terms, expressed as a rate ratio.Changes to seasonality in 2020 were primarily assessed by changes in the extent of seasonal variation .The data underlying this article are available in the Australian Bureau of Statistics Provisional Mortality Statistics, at [IJE online.G.G. contributed to conceptualization, did the data analysis, contributed to data interpretation and wrote the original draft of the manuscript. L.Z. did the data analysis, contributed to data interpretation, contributed to supervision and reviewed and edited the manuscript. A.H. contributed to data interpretation, contributed to supervision and reviewed and edited the manuscript. K.B. conceived of the study, contributed to data interpretation, was primary supervisor and reviewed and edited the manuscript.There was no specific funding for the study. K.B. is supported by an Australian National Health and Medical Research Council (NHMRC) Investigator Grant (#1174523).None declared.dyac032_Supplementary_DataClick here for additional data file.


Low klotho is associated with aging-related traits. However, no study has assessed the association between klotho and oral health in a large sample of population. This study aimed to explore the association between serum α-klotho and oral health in US Adults.Data were from the National Health and Nutrition Examination Survey. Oral health parameters included periodontitis, self-rated oral health, and tooth loss. Logistic regression and restricted cubic spline models were adopted to evaluate the associations.P <0.01). Compared with the highest tertile, the lowest tertile of α-klotho was associated with moderate/severe periodontitis, poor-rated oral health, and tooth loss, with OR (95% CI) being 1.21 , 1.26  and 1.38 , respectively. An increment of per 1 standard deviation in the α-klotho concentration was associated with lower odds of moderate/severe periodontitis . Linear dose-response relationships were found between α-klotho and the odds of moderate/severe periodontitis (P for non-linearity=0.88) and poor-rated oral health (P for non-linearity=0.66). An L-shaped dose-response relationship was found between levels of α-klotho and the odds of tooth loss (P for non-linearity=0.04).A total of 6187 participants were included in the study. The median of the α-klotho level was 815.2 pg/mL. Serum α-Klotho was significantly lower in participants with poor oral health (all Serum α-klotho was associated with oral health. Further studies are necessary to clarify the potential mechanisms and demonstrate the predictive ability of klotho in oral diseases. Oral disease has become a serious public health issue worldwide , 2. The Klotho protein, a multifunctional protein with antiaging properties, is predominantly expressed in the kidney, parathyroid glands, and choroid plexus of the brain. Secreted klotho is involved in a variety of physiological processes through various mechanisms, such as regulation of serum levels of phosphate and vitamin D, acceleration of oxidative stress , 20, etcThus, we used data from the National Health and Nutrition Examination Surveys (NHANES) to examine the association between serum α-klotho and oral health and further explore the strength of association in stratified analyses across related characteristics among a nationally representative sample of adults from the United States.1. There are non-significant associations of low serum α-klotho with moderate/severe periodontitis, poor-rated oral health, and tooth loss.2. The dose-responses relationships of serum α-klotho with the risk of moderate/severe periodontitis, poor-rated oral health, and tooth loss are linear.The NHANES is a national program to assess the health and nutritional status of the US sample. A multistage and stratified sampling method was used to identify the participants with good representativeness. Recruited participants were invited to complete standardized questionnaires and undergo a physical examination by laboratory testing after providing written informed consents. Socio-demographic characteristics, physical examinations , dietary information, and laboratory data were collected. The study protocol was approved by the National Center for Health Statistics Research Ethics Review Board (Protocol #2005-06 and Protocol #2011-17).Data were combined across 4 continuous NHANES cycles: 2007-2008, 2009-2010, 2011-2012, 2013-2014. Stepwisely excluded those aged <40 or >79 years (n=26618), those with missing data on α-klotho (n=2871), and those with missing data on oral measures , a total of 6187 participants aged 40-79 years with complete information on α-klotho and oral measures were included in the final analysis. The inclusion and exclusion flowchart of the study population is presented in °C and serum α-klotho was measured among participants aged from 40 to 79 years old. Strictly following the manufacturer’s protocol, serum α-klotho was assayed using a solid-phase sandwich enzyme-linked immunosorbent assay . This assay is reported to have a sensitivity of 6 pg/mL. All sample analyses were performed twice and the average of the two values was calculated as the final value of serum α-klotho. More details regarding the laboratory methodology of α-klotho concentrations determination can be available on the NHANES website. In our analyses, α-klotho was categorized by tertiles.Blood samples were stored at -80via responses to the single item: “how would you rate the health of your teeth and gums?” The participants chose one of the following responses: “excellent”, “very good”, “good”, “fair”, or “poor”. Self-rated oral health was categorized as good-rated oral health (excellent/very good/good), and poor-rated oral health (fair/poor). The number of teeth was categorized as a 2-level category, and tooth loss was defined as the number of teeth remaining <21 based on the literature review , diabetes mellitus, and hypertension. Educational level was categorized into two groups . Marital status was categorized into two groups . Drinking status was defined as <12 or ≥12 alcohol drinks per year . Physica2 and overweight/obese: ≥24.9 kg/m2), physical activity (high or low/moderate), the status of hypertension (yes or no), and the status of diabetes mellitus (yes or no). In addition, the shape of the dose-response relationships was explored using restricted cubic splines (RCS) with three knots at the 25th, 50th, and 75th percentiles. All statistical analyses were performed using Stata v14.0.The differences in sample characteristics across the tertiles of α-klotho were compared using ANOVA for continuous variables and chi-square tests for categorical variables, respectively. Logistic regression models were used to estimate the odds ratios (ORs) and 95% corresponding confidence intervals (CIs) for oral health parameters. α-Klotho was examined as both a continuous variable and a categorized variable (the highest tertile group was used as the reference group). Model 1 initially adjusted for age and sex. Model 2 adjusted for race, educational level, marital status, family poverty income ratio, smoking status, drinking status, physical activity level, BMI, diabetes mellitus, hypertension, and eGFR, additionally. We also conducted stratified analyses by potential factors, including sex, age (<60 and ≥60 years), BMI .The characteristics of the study participants are shown in P for trend =0.01). An increment of per 1 standard deviation in α-klotho was associated with lower odds of moderate/severe periodontitis .The associations of α-klotho with oral health parameters are presented in P for non-linearity =0.88) and poor-rated oral health (P for non-linearity =0.66). An L-shaped dose-response relationship was found between α-klotho and the odds of tooth loss (P for non-linearity =0.04), suggesting that under the highest tertile of α-klotho concentration, the odds of tooth loss increase with the decline of the serum α-klotho concentration.The dose-response relationship of serum α-klotho level with oral health is presented in The stratified analysis of the association between α-klotho and oral health is shown in In the present study, we explored the association between α-klotho and oral health among a nationally representative sample of U.S. adults. The levels of α-klotho were significantly lower in participants with poorer oral health than those in their counterparts. Meanwhile, low α-klotho was associated with increased odds of moderate/severe periodontitis, poor-rated oral health, and tooth loss. And, the associations between α-klotho and oral health parameters were presented in dose-response manners. Furthermore, stratified analyses demonstrated the association of α-klotho with oral health across diverse subgroups.The observed association between klotho and oral health in our study was consistent with previous studies. A cross-sectional study conducted in China showed that compared with those in the healthy counterparts, the levels of klotho in the gingival crevicular fluid and gingival tissues of chronic periodontitis patients were significantly lower . Another2O2, the level of reactive oxygen species (ROS) and malondialdehyde were both reduced, meanwhile, the activity of antioxidant enzymes  was restored, by the treatment of klotho protein in hPLSC. Moreover, the expressions of apoptotic-related proteins (including BAX and Caspase-3) in hPLSCs were also reduced by the addiction of klotho  , 40, whif klotho , 40. Thuf klotho , 35, whif klotho . Animal f klotho , 35. Thif klotho . Lower cf klotho .In stratified analyses, we found that low α-klotho was associated with poor-rated oral health and tooth loss only in females. This might be explained by the effect of sex hormone change in menopause among females. A longitudinal study of 1341 postmenopausal women with a mean follow-up of 5.1-year showed that 28.7% of participants lost at least one tooth during follow-up . BesidesOur study examined the association between α-klotho and oral health based on a nationally representative sample, which facilitates the generalization of the findings. Second, the dose-response relationships in our findings help us to evaluate how the odds of oral conditions change with the continuous decrease of α-klotho. However, several limitations of our study should be noted. First, the cross-sectional design does not allow us to infer causation between α-klotho and oral diseases or conditions and to examine whether the klotho level could be corrected to improve oral health. Second, confounding factors, including dental visits, and history of head and neck radiotherapy were not assessed in the present study,which might have influenced our findings. Third, due to the constraints of the NHANES database, the parameters of oral health were not defined comprehensively: 1. Periodontitis was defined by clinical attachment loss and probing pocket depths without consideration of saliva or gingival crevicular fluid in our study. 2. Tooth loss was simply defined by the number of remaining teeth, overlooking the cause of the tooth loss in the present study. Fourth, as shown in In conclusion, we found that serum α-klotho is associated with oral health in US adults. And the association presents in a dose-response manner. It may be of significant public health and clinical importance that provide new insights into the implication of klotho in oral diseases. Further studies are necessary to clarify the potential mechanisms underlying the association and demonstrate the predictive ability of α-klotho in oral diseases.The datasets presented in this article are not readily available because of privacy or ethical restrictions. The data used and analyzed during the present study are available from the corresponding author on reasonable request.The study protocol was approved by the National Center for Health Statistics Research Ethics Review Board. The patients/participants provided their written informed consent to participate in this study.X-LY and G-QC conceived and designed the study. G-QC analyzed the data and wrote the manuscript. YL, J-FW and YD provided comments and technical advice. All authors revised the manuscript critically for important intellectual content, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.This work was supported by Shandong Provincial Key Research and Development Program (grant no. 2019GSF108196), Center of China–US Sports Economics and Health Engineering of Shandong (grant no. SDCA20191013), Academic Promotion Programme of Shandong First Medical University (grant no. 2019QL013).We gratefully acknowledge all of the study participants and staff for their assistance during the study.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Among the groups, only the TSC-OP–silane treatment effectively enhanced the bond strength and maintained the adhesion after thermocycling. With these results, the OP aided the silicatization protocol effectively, generated silane crosslinking, and resulted in superior resin–zirconia bond strength and durability compared to the current treatments.The combinations of alumina particle air abrasion (AA) and a 10-methacryloyloxyidecyl-dihyidrogenphosphate (MDP) primer and a tribochemical silica coating (TSC) and a silane–base primer are contemporary pre-cementation treatments for zirconia restorations for bonding with resin cements. However, the stability of zirconia resists the mechanical or chemical preparations. The purpose of this study was to develop an atmospheric-pressure oxygen plasma (OP)-aided silicatization method to enhance the adhesion of resin cements to zirconia. Zirconia discs were prepared to receive surface treatments of different combinations: (1) AA or TSC (2) with or without OP treatment, and (3) a chemical primer . The surface morphology, hydrophilicity, and chemical compositions were characterized, and the resin–zirconia bond strengths were examined either after 24 h or a thermocycling test. The results indicated that the OP treatment after the TSC facilitated the homogeneous distribution of silane and crosslinking of silica particles, and effectively improved the hydrophilicity. The OP increased the O and Si and reduced the C elemental contents, while the combination of TSC, OP, and silane induced SiO In recent decades, dental metal–ceramic restorations have been replaced with ceramic systems due to the rising costs of precious metals and the unpleasing opacity of metal copings . Yttria-Silicatization is another approach to increase the surface reactivity of zirconia. Selective infiltration etching was developed based on heat-induced nano-structural changes to allow the diffusion of a specific molten glass into the zirconia. The fused silica phase is subjected to HF etching to be retentive, whereby the adhesive resin monomers can infiltrate and interlock . Other s2O and CO2 [Plasma technology has been widely applied in biomedical engineering and is recognized as an economical and effective method for surface modifications . Plasma  and CO2 ,27. Base and CO2 ,26,28,29 and CO2 ,31.The use of a TSC together with silanization has been a common silicatization approach for adhesion substrates, regardless of the non-uniformity and small fraction of surface coverage . The plaCercon zirconia blank cylinders  were cut into disks (19.5 mm in diameter and 2.5 mm in thickness) and divided into eight pieces. A total of 200 pieces were generated and fully sintered. These specimens were polished serially using 320-, 400-, and 600-grit silicon carbide papers. The polished specimens were placed in 95% alcohol, subjected to ultrasonic cleaning for 5 min, and then dried. Afterward, the specimens were divided into ten groups to receive different combinations of surface treatments: (1) grit blasting treatment: alumina particle air abrasion (AA) or TSC, (2) with or without APOP treatment; (3) primer treatment: no primer, with a silane–base or silane–MDP mixture primer. The treatments for the experimental groups are illustrated in 2O3 particles  at a distance of 10 mm for 15 s at 2.5 bar pressure. The specimens were ultrasonically cleaned in deionized water three times each for 10 min. Subsequently, they were dried using an oil-free air gun. For the TSC treatment, the zirconia specimens were grit-blasted at the same distance with 30 μm silica-coated Al2O3  at 2.8 bars for 15 s.For the AA treatment, the zirconia disks were grit-blasted utilizing 45 µm AlIn the 2nd step of the surface treatments, half of the specimens were subjected to APOP treatments using a pen-style atmospheric-pressure oxygen plasma jet . The plasma jet consisted of two concentric cylindrical stainless-steel electrodes. The outer electrode was 18 cm long, with a 25 mm inner diameter and a converging nozzle with a diameter of 2.5 mm. The plasma was generated using an oxygen gas flow at 9.5 L/min, under a pulse power excitation of up to 80 W. The assigned zirconia disks were placed 5 mm under the plasma jet to receive the gas stream for 30 s. During the plasma treatment, the surface temperature of the specimens reached 160 °C. The OP-treated specimens received their assigned primers after 2 s, when their temperature decreased to approximately 80 °C.The last step of the surface treatment involved the chemical modifications. To investigate the silicatization caused by different agents, the specimens were divided into three subgroups: no primer, a silane–base primer (S), or an experimental primer in the form of a mixture (M) of silane and MDP. For groups AA, AA-OP, TSC, and TSC-OP, no primer was applied. For groups AA-S, AA-OP-S, TSC-S, and TSC-OP-S, the zirconia disks were coated with 12 µL of the silane–base primer Clearfil Porcelain Bond Activator  for 5 s using a micropipette, and dried using the oil-free air gun. For groups AA-M and AA-OP-M, an experimental primer of the MDP–silane mixture was prepared following our previous work . Equal vThree treated specimens in each group were gold-sputtered and then observed under a low–variable vacuum scanning electron microscope . In the preliminary micromorphologic findings, only TSC-S and TSC-OP-S showed the presence of surface coatings. Therefore, the zirconia specimens in these two groups were further examined under a field-emission SEM  at high magnification.n = 5). The contact angles were then analyzed using ImageJ software.To examine the changes in the hydrophilicity of each specimen, 2 µL of deionized water was dispensed on the specimen surfaces as the probing liquid. A charge-coupled device camera was employed to capture the images of the contact angles on the specimen surfaces . The specimen was placed in a vacuum chamber under 5 × 102 with a quartz halogen light unit  for 40 s from different directions. The light intensity was verified using a radiometer . The specimens were left to set for 30 min and placed in a 37 °C water bath for 24 h. Subsequently, half of the specimens (n = 10) in each group received the early (T0) SBS test, and the other half (n = 10) were subjected to 6000 thermocycles (T6000). The thermocycles consisted of alternative soaking in 5 °C and 55 °C deionized water baths, with a 30 s dwelling time at each temperature and a 5 s transfer time between the two baths. For the SBS test, the resin–zirconia assemblies were fixed on the jig of a universal material test machine . Force was applied near the bond interface using a chisel at a crosshead speed of 1 mm/min until fracture. After the SBS test, the zirconia specimens were sectioned to inspect the bond interface between the zirconia and the adhesive layers.The resin–zirconia bonding was examined using early and post-thermocycling shear bond strength (SBS) tests. In each group, twenty zirconia disks were prepared and treated with the assigned treatments. Pre-cured resin composite tablets (3-mm-diameter and 2-mm-thick) were fabricated using a microhybrid resin composite named Filtek Z250 . An adhesive cellulose acetate tape with a 3 mm hole was attached to the zirconia surface. A dual-cure resin luting cement  was filled in the hole, and the composite tablet was cemented and loaded under 5 N of force. The excess resin cement was cleaned, and the tape was carefully removed. The cemented specimen was light-cured at 850 mW/cmt test was conducted to examine the effects of the thermocycling on the SBSs. The significance level was set at p < 0.05.The statistical analysis was performed with SPSS 20.0 . The contact angles in the wettability test and the SBSs of all experimental groups were analyzed using a one-way analysis of variance (ANOVA) followed by a post hoc Duncan test. An additional three-way ANOVA test was performed to assess the individual effects of the grit blasting, APOP processing, primer agents, and their interactions on the SBSs. An independent samples Under SEM, the treated zirconia specimens showed roughened surfaces . All AA 2 particles.The micromorphology of the TSC-treated specimens was further examined at higher magnification  . TSC-alop < 0.05) (The results from the contact angle test identified significant differences among the groups ( < 0.05) . AA-alonAll of the TSC-treated groups showed high hydrophilicity (contact angles less than 12°). The TSC-OP group even showed superhydrophilicity, with unmeasurable contact angles. Similar to AA-S and AA-OP-S, the silane conditioning following TSC also increased the contact angles, but only to a minor degree.2O3 particles. Weak P 2p signals were present in AA-M and AA-OP-M.The XPS spectra of the eight experimental groups are illustrated in 3)2)O) at 533.6 eV.Fine scanning of the individual O 1s peaks was performed to analyze the chemical state of the treated zirconia b. The O The elemental compositions are listed in 2O3 (102.5 eV), SiO2 (103.5 eV), and SiO4 (104.1 eV) , SiO (101.5 eV), Si04.1 eV)    [29,30,3p < 0.05) improved the bonding strengths. In the T0 SBS test, the AA-OP-M and TSC-OP-S groups exhibited higher SBSs, followed by AA-M and TSC-S . AA-alont test showed that all groups had dramatic reductions in SBSs after thermocycles, with the exception of the AA-OP-S and TSC-OP-S groups. Actually, TSC-OP-S exhibited a comparable SBS to its T0 counterpart.After 6000 thermocycles, all AA-alone specimens failed before the test. The AA-OP and AA-S groups also showed low bond strengths , while AA-OP-S exhibited a much higher SBS (16.7 MPa). The p < 0.001) influenced the SBS at both T0 and T6000 stages. For the T0 SBSs, there were interactions between the mechanical abrasion and OP treatment, as well as between the primer and the OP treatment. In terms of the T6000 SBSs, there was no interaction between any two factors.According to the three-way ANOVA test, either the priming conditions, OP treatment, or thermocycling test substantially  and light-cured immediately after sitting. A previous study revealed that the light activation of the dual-cure cement resulted in better bonding performance compared to the self-curing mode . Even wiAmong the groups, only TSC-OP-S effectively enhanced and sustained the SBSs after thermocycling. The OP-aided silicatization method has multiple benefits in enhancing the resin cement’s adhesion to zirconia. As the TSC generated a partially fused silica coating on the surface, the APOP gas flow removed the loose silica coatings but left the bonded ones. The heat melted the coatings and transformed them into dense clusters or tightly silicate layers . These pWith the above findings, the first hypothesis was rejected. The type of grit blasting, use of APOP, and use of a chemical primer all affect the bond performance. The second hypothesis was also rejected, since the APOP had a synergistic effect on improving the adhesion when combined with the TSC or a silane agent, but had an antagonist effect when combined with the MDP. Among the groups, the protocol using the TSC then APOP and silane lead to strong resin–zirconia bonding and favorable durability. The incorporation of the APOP between traditional TSC–silane treatments facilitates surface silicatization, which could be an effective pre-cementation treatment for dental zirconia restorations to establish reliable adhesion with resin cements. With the advances in plasma technology, various micro-plasma jet systems can be applied for this purpose. In this regard, this study still presents limitations, since various AP conditions were not examined. Future research about the source gas and operating parameters may provide in-depth information about the plasma species concentration, and the species’ effects on the surface modifications and mechanical properties of the zirconia. Additionally, this study did not assess the combination of a TSC, APOP, and silane–MDP mixture. The interpolation between the primers and APOP-assisted silicatization should be explored for further improvement of the adhesion of resin cement to zirconia restorations.This study developed a new silicatization method for dental zirconia restorations via serial treatments of a TSC, APOP, and a silane coupling agent. This method avoids the problems of adhesion hydrolysis associated with AA-M treatments and incomplete silica coatings caused by TSC. The reactive oxygen species generated by the APOP may clean the organic pollutant and loosen the silica coating, and the residual heat strengthens the crosslinking of the silica coating and silane. Accordingly, an intact bond interface is formed, which leads to strong and durable resin–zirconia bonding. With the initial findings, the incorporation of APOP with AA or a silane–MDP mixture primer may enhance the initial bond strength, but the APOP has no effect on the performance against thermocycling. In this regard, the APOP is not recommended to be combined with MDP-based or universal adhesives.


Multivariate analysis showed that PN (≥Grade 2) was not a significant factor affecting either OS (hazard ratio (HR) 0.66, 95% confidence interval [CI] 0.33–1.31, p = 0.24) or TTF . No significant difference was observed in the relative dose intensity of GEM or nab-PTX, and incidence of adverse events. Conclusions: mFFX-induced PN has little impact on the efficacy and safety of second-line GnP in patients with APC. Second-line GnP could be a possible treatment option regardless of the presence of PN.Modified FOLFIRINOX (mFFX) and Gemcitabine plus nab-paclitaxel (GnP) are effective first-line chemotherapies for unresectable advanced pancreatic cancer (APC); however, both lead to peripheral neuropathy (PN). Aims: To evaluate the impact of first-line mFFX-induced PN on the efficacy of second-line GnP in patients with APC. Methods: A database containing patients with APC was retrospectively analyzed to evaluate patients who received second-line GnP after first-line mFFX failure between September 2014 and January 2021. The efficacy and safety of GnP were compared between patients with PN ≥ Grade 2 (PN group) and PN ≤ Grade 1 (non-PN group) at the start of second-line GnP. Cox proportional hazards analysis was also performed to examine the effect on overall survival (OS) and time-to-treatment failure (TTF). Results: Fifty-nine patients  were included. Median OS and TTF in the PN versus non-PN group were 7.7 versus 5.7 months ( Pancreatic cancer (PC) is the seventh leading cause of cancer-related death in the world, with a five-year survival rate of 11% . The proL-OHP, a platinum-based anticancer agent used in mFFX, and nab-PTX, a taxane-based anticancer agent used in GnP, are known to cause high rates of peripheral neuropathy (PN). The incidence of PN in patients treated with mFFX and GnP is 75% (≥Grade 3: 5.6%) and 54% (≥Grade 3: 17%), respectively [This retrospective observational study was conducted at a single center, Gifu University Hospital. We analyzed a database containing patients with APC receiving chemotherapy between September 2014 and January 2021 to identify patients who met the following criteria: (1) GnP was performed as second-line treatment after failure of FFX for APC; and (2) pancreatic cancer was pathologically proven to be ductal adenocarcinoma. No exclusion criteria were set for this study. The efficacy and safety of GnP were compared between the two groups at the start of GnP in patients with PN ≥ Grade 2 (PN group) and PN ≤ Grade 1 (non-PN group). Tumor response was evaluated using computed tomography (CT) scans as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Treatment response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 . The oveCIPN was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 . Grade 1The primary endpoint was OS. Secondary endpoints were a time-to-treatment failure (TTF), response rate (RR), relative dose intensity (RDI), adverse events (AEs), and change in the severity of PN. OS was calculated from the start date of second-line GnP to the date of death. TTF was calculated from the start date of second-line GnP to the date of GnP discontinuation. Patients without the event of death or treatment discontinuation were censored at the time of the last follow-up. During the treatment period, patients were assessed for their general condition and AEs by physical and blood examinations. AEs were graded based on the CTCAE version 5.0 . The mosp values lower than 0.05 were considered statistically significant. The Cox proportional hazards model was used to examine factors associated with OS and TTF. Possible factors included the presence or absence of PN, age, sex, metastasis, CA19-9 (carbohydrate antigen 19-9), and cumulative dose of L-OHP (mg/m2). All statistical analyses were performed using EZR  and GraphPad Prism version 9.3.1 .Continuous variables are expressed as median (range) and were compared using the Mann–Whitney U test. Fisher’s exact test and Pearson’s chi-squared test were used to compare categorical variables. OS and TTF were estimated using the Kaplan–Meier method and compared using the log-rank test. For each test, This study was conducted in accordance with the guidelines for human studies adopted by the ethics committee of Gifu University Graduate School of Medicine and notified by the Japanese government . In view of the retrospective nature of the study, subject informed consent was not required. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.During the study period, 100 patients with APC received mFFX as first-line treatment. Ten patients continued with mFFX to the end of the study period and four patients underwent conversion surgery because of a good response to mFFX. After treatment failure with first-line mFFX, 72 patients underwent second-line treatment, 12 patients did not receive further treatment, and 2 patients were transferred to other hospitals. Second-line regimens included GnP in 59 patients, GEM in 9 patients, and S-1 in 4 patients. The reasons for no GnP regimen as second-line were the deteriorated PS in 12 patients and CIPN of grade 2 in 1 patient. The 59 patients who underwent GnP as second-line treatment were included in our analysis . Of the 2 versus 617.4 mg/m2, p = 0.03) and the proportion of patients taking pregabalin/mirogabalin-containing treatment was significantly higher in the PN group compared to the non-PN group .The baseline characteristics of the patients are shown in p = 0.39). The median RDIs of GEM and nab-PTX were not significantly different between the PN group and non-PN group . Likewise, median OS and TTF were not significantly different   (p = 1.0) and the DCR was 38.9% and 36.6% in the PN group and non-PN group (p = 1.0), respectively.The median OS and TTF were 6.3 months  and 3.2 months (95% CI: 2.1–3.9), respectively. As shown in  = 0.18) . Cox pro = 0.28) . The ORRp = 0.27). As shown in p = 0.31). There were no significant differences in other Grade 3 or higher AEs between the two groups. Reasons for discontinuation of GnP (PN versus non-PN group) were PD in 16 patients (88.9%) versus 39 patients (95.1%), and AEs in 2 patients  versus 2 patients . The change in the severity of PN from the start to the end of GnP therapy is shown in The incidence of AEs ≥ Grade 3 was not significantly different between the PN group and non-PN group  in the PN group, although it tended to occur more frequently in the non-PN group (19.5%: Grade 0/1 to Grade 2). However, no treatment discontinuation occurred because of PN-related reasons. Yamaguchi et al. studied the change in PN in patients with advanced gastric cancer who received first-line L-OHP-based regimens and second-line PTX treatment, which is similar to the mFFX followed by the GnP regimen examined in this study. The severity of PN at the end of first-line treatment (≥Grade 2 versus ≤Grade 1) did not significantly affect the incidence rate of PN ≥ Grade 2 during second-line PTX ,21. Furtp < 0.001). Considering that 50% of patients in the PN group received pregabalin or mirogabalin, it is possible that pregabalin or mirogabalin may have reduced the symptoms of PN or prevented potential progression caused by taxanes. Based on these results, early supportive therapy with duloxetine, pregabalin, and mirogabalin for L-OHP-induced PN might be important for maintaining the efficacy and safety of second-line GnP after the failure of mFFX in patients with APC.In terms of the management of PN, a previous study reported the efficacy of duloxetine as supportive therapy for CIPN, especially with platinum-based anticancer agents . PregabaThis study has several limitations. First, this was a retrospective study that examined a small cohort at a single center. This study design may be associated with bias in patient selection and limit external validity. Second, since this study did not include patients with PN ≥ Grade 3, the effect of GnP on more severe PN could not be evaluated. Third, there may have been potential discrepancies between assessments by medical staff and actual PN symptoms, since PN is reportedly one of the most subjective AEs and is often prone to underestimation by medical staff . Use of In conclusion, the severity of PN induced by first-line mFFX likely has little impact on the efficacy and safety of second-line GnP in patients with APC. Therefore, second-line GnP administered after mFFX may be an effective treatment option regardless of the presence of PN, although further large-scale studies are required to confirm our findings.


Heparin has shown benefits in severe acute pancreatitis (SAP) therapy, but the underlying mechanisms were unknown. Extracellular high-mobility group protein-1 (HMGB-1) has been regarded as a central mediator contributing to inflammation exacerbation and disease aggravation. We hypothesized heparin attenuated the disease by targeting HMGB-1-related pathways. In the present study, the possible therapeutic roles of heparin and its non-anticoagulant derivatives, 6-O-desulfulted heparin and N-acylated-heparin, were determined on mouse models induced by “Two-Hit” of L-arginine. The compounds exhibited potent efficiency by substantially decreasing the pancreatic necrosis, macrophage infiltration, and serum inflammatory cytokine (IL-6 and TNF-α) concentration. Moreover, they greatly reduced the rapidly increasing extracellular HMGB-1 levels in the L-arginine injured pancreases. As a result, multiple organ failure and mortality of the mice were inhibited. Furthermore, the drugs were incubated with the RAW264.7 cells activated with damaged pancreatic tissue of SAP mice in vitro. They were found to inhibit HMGB-1 transfer from the nucleus to the plasma, a critical step during HMGB-1 active secretion from macrophages. The results were carefully re-examined with a caerulein and LPS induced mouse model, and similar results were found. The paper demonstrated heparin alleviated SAP independent of the anti-coagulant functions. Therefore, non-anticoagulant heparin derivatives might become promising approaches to treat patients suffering from SAP. Acute necrotizing pancreatitis is associated with the high rates of morbidity and mortality of severe acute pancreatitis (SAP). The disease often develops in a cascade of inflammatory reactions, sepsis, and multiple organ dysfunction, and is associated with a mortality rate of 8~39% after a “second hit” . There hDuring the development of SAP, extracellular high-mobility group protein-1 (HMGB-1) was recognized as an important predictor of the disease . It is uHeparin, an important group of antithrombin agents, has shown benefits during SAP treatment; they were able to reduce the incidence of pancreatic encephalopathy and improve the survival percentage both as monotherapy and in combination with other drugs ,10,11. SHowever, heparin is also regarded as an important anti-inflammatory agent with multiple molecular targeting properties though its high affinity with a variety of chemokines, cytokines, and growth factors . It reprIn this paper, we hypothesize that heparin alleviated SAP by targeting the HMGB-1 related pathway. We compared the efficacy of heparin, 6-O-desulfulted heparin (6-desO H), and N-acylated-heparin (N-actyl H) on an SAP mouse model with a “Two-hit” of L-arginine. Then, the related signaling pathway was investigated in vitro with activated RAW264.7 cell lines. Finally, the results were re-examined with a caerulein and LPS induced SAP mouse model. We concluded that heparinoid alleviated SAP by inhibiting HMGB-1 secretion from the pancreatic macrophages .L-Arginine was purchased from Bomei Pharmatech Ltd. . Mouse IL-6 and TNF-α enzyme-linked immunosorbent assay (ELISA) kits were from Proteintech . FITC labeled Dextran  was purchased from Xi’an Ruixi Biological Technology Co., Ltd. . Mouse HMGB-1 ELISA kits were purchased from Sangon Biotech . The Hematoxylin and Eosin (H&E) Staining Kit was purchased from Abcam . The anti-HMGB-1 rabbit polyclonal anti-body was purchased from Sangon Biotech. . Lipase activity and α-amylase activity assay kits were from Jiancheng Biotech . Caerulein was purchased from Nanjing Peptide . Lipopolysaccharide (LPS) was purchased from Aladdin .The Animal Research Committee of Jiangnan University approved all the animal experiments. Male ICR mice (8 weeks) were purchased from Cavens Laboratory Animal CO.LTD .For the L-arginine induced SAP model, 37 mice were divided into the following five groups: the SAP group (n = 16), the heparin group (n = 14), the 6-desO H group (n = 14), the N-acetyl H group (n = 14), and the control group (n = 5). They had free access to food and water during the whole project.w/w, pH = 7.4) was incubated in ice-cold water and injected intraperitoneally into the mice twice at an interval of one hour, with each dosage of 4 g/kg (approximately 1.3 mL). The mice were allowed to recover for 72 h and were then repeatedly subjected to L-arginine injection after the first-round operation. The group that received the identical PBS injections were used as control group.The mouse model was set up according to the published paper . L-arginThe heparin, 6-desO H, and N-acetyl H groups were intraperitoneally administered with drugs (0.5 mg/kg) 1 h after the first L-arginine injection and received drug treatment every 24 h. Meanwhile, the SAP group and the control group received 0.1 mL of PBS buffer.Blood was drawn from the mice, and they were sacrificed 24 h after the last time of L-Arginine induction. The pancreatic, lung, and intestinal tissues were taken out for further analysis. However, eight mice of the SAP and drug-given groups were allowed to remain in the cage for 80 h, which was used to calculate the survival rate in response to L-arginine challenge.Twenty-five ICR mice were used for the caerulein and LPS -induced SAP model setting. They were divided into the following five groups: the SAP group (n = 5), the heparin group (n = 5), the 6-desO H group (n = 5), the acetyl H group (n = 5), and the control group (n = 5). The mice were intraperitoneally injected with caerulein (200 µg/kg) each hour during a periold of 10 h, followed by LPS (5 mg/kg) administration 1 h after the last caerulein injection. They were free to access food and water during the whole project. The group that received the identical PBS injections were used as control group.The heparin and its derivative groups were intraperitoneally administered with drugs (0.5 mg/kg) 1 h after the first caerulein injection. Meanwhile, the SAP group and the control group received 0.1 mL of PBS buffer. Blood was drawn from the mice, and they were sacrificed 12 h after LPS administration. The pancreatic tissues were taken out for further analysis.Hungary). Two investigators who were blind to the experimental treatment scored the pancreatic necrosis degree according to the published scoring standards [Fresh tissues were fixed in 4% paraformaldehyde and embedded with paraffin. H&E staining was performed according to the published papers . The pattandards . TUNEL sHungary).The fresh pancreas was fixed, sliced, dewaxed, rehydrated, underwent antigen retrieval, were blocked with 5% BSA, and stained with the antibody of HMGB-1 or CD68. The IHC procedures were performed according to the standardized process . Finally2 had been added. The product could then be measured based on the absorption at 660 nm.The blood from mice was collected and centrifuged  to obtain the supernatant. Serum activity of α-Amylase and Lipase were detected using assay kits. All the kits were used according to the manufacturer’s instructions. Briefly, the lipase catalyzed the hydrolysis of oil esters into fatty acids, and the production rate was determined by the copper soap method based on the absorbance of at 715 nm. α-Amylase cleaved the substrate in serum to produce smaller fragments with the ability to form chromophore after ISerum TNF-α, IL-6 and HMGB-1 were measured by ELISA kits  according to the manufacturer’s protocols.Intestinal permeability was measured as described previously . Six hou2. The cells were pretreated with heparin and its derivatives (50 μg/mL) before stimulation with supernatant of the pancreatic tissue from the “Two-Hit” model mice for 2 h (5 μL in 1 mL culture media).RAW264.7 cells were purchased from Cobioer Biosciences Co., Ltd. , cultured in DMEM with 10% FBS and 1% Penicillin-Streptomycin solution and maintained in a humidified atmosphere at 37 °C with 5% CORAW 264.7 cells were plated on coverslips and cultured overnight. Two hours after treatment with pancreatic tissue supernatant and drugs, the cells were fixed, permeabilized, and blocked with 5% BSA. Cells were then incubated with mouse anti–HMGB-1 primary antibody (1:200 dilution) overnight at 4 °C, followed by incubation with Alexa Fluor 488 conjugated goat anti-rabbit secondary antibody for 45 min. Nuclei were counterstained with DAPI. Images were recorded using a Carl Zeiss LSM880 microscope (USA).Two hours after treatment with pancreatic tissue supernatant and drugs, the cells were harvested by centrifuge (1500 rpm/min for 5 min). Total cellular proteins were isolated. Western blot analysis was performed using specific primary antibodies and horseradish peroxidase–conjugated secondary antibodies, as described previously . Immunorp < 0.05. All the analyses were conducted using GraphPad Prism 8 software.Data were expressed as mean ± SEM. Difference among multiple groups was assessed using one-way variance followed by the Bonferroni’s Multiple Comparison Test. The results were considered statistically significant at 1H-NMR and 13C-NMR spectra were recorded and compared with the published paper  is one of the most serious complications during SAP development . In the To investigate whether heparin inhibited HMGB-1 active secretion from macrophages, the drugs were incubated with the activated RAW264.7 cells. HMGB-1 usually binds with DNA in the nuclei of the cell, transfers to the cell cytosol, and finally exits the cell under stress. The immunological fluorescence assay found the HMGB-1 concentrated in the nuclear zone of the normal control cell, whereas it shifted and diffused in the cytoplasm in the SAP group A. The alWe then re-evaluated these effects on the most widely recognized SAP model induced by cerulein and LPS . The hisWith the continued increasing incidence of SAP, the drug development for the disease therapy is urgent. Recently, heparin has shown to attenuate the pancreatic damages. The involved pathogenesis is unknown, and only attributed to the prevention of splanchnic thrombosis . HoweverIn this paper, we prepared the non-anticoagulant form of heparin and evaluated its effects on the mouse model induced by “Two-hits” of L-arginine. All the drugs substantially alleviated the pancreatic necrosis and strongly reduced the macrophage recruitment and the cytokine levels. As pancreatic necrosis was considered an absolute indication of poor prognosis of the patients, this was the key cellular processes for heparin to control the pathogenesis of SAP .HMGB-1 is a constitutive protein that stabilizes nucleosomes in almost all cell lines in normal tissues. It is passively released during cell necrosis, or actively released from immune cells stimulated by pro-inflammatory mediators ,28. The Some researchers have reported that heparin reduced the amplification of several other inflammatory responses induced by HMGB-1 by interacting with HMGB-1 directly , or inteIndeed, extracellular HMGB-1 was found in a huge amount in the pancreas of the SAP group, indicating the disease progressed into serious conditions. The drug administration substantially reduced the extracellular HMGB-1 levels. Consequently, the multiple organ failure  had been blocked and the mortality was decreased.Furthermore, as macrophages were regarded as the main source of extracellular HMGB-1, we investigated whether heparin inhibited HMGB-1 secretion from macrophages . We incuThen, the conclusion was carefully re-examined with a caerulein and LPS induced SAP model. Similarly, the drugs alleviated reduced the acinar cell swollen and necrosis in pancreas and reduced the serum TNF-α concentrations due to decreased HMGB-1 levels in the pancreas tissue. The results were consistent with the ones obtained on L-arginine induced SAP.In summary, we evaluated the therapeutic effects of heparin and its non-anticoagulant derivatives on SAP mouse models and investigated the related mechanisms. We found they effectively alleviate the pancreatic necrosis and high inflammatory state by blocking HMGB-1 active secretion from macrophages, demonstrating that heparin exerted the effects independent of the anti-coagulant function. Given the safe profile of the non-anticoagulant heparin derivatives, they might replace heparin and become promising approaches that treat patients suffering from SAP.


After familiarisation and basal measurements, participants attended the laboratory on two occasions separated by 72 h to receive either Sham or a-tDCS (current intensity of 2 mA for 20 min). Immediately after stimulation, participants completed three sets of 12 repetitions (70% of 1-RM) with three minutes of recovery between sets monitored with a linear position transducer. The sEMG of the rectus femoris (RF) and vastus lateralis (VL) of both legs were recorded. No significant differences were observed between a-tDCS and Sham interventions on mean concentric velocity at any set (p > 0.05). Velocity loss and effort index were significantly higher (p < 0.05) in set 3 compared to set 1 only in the a-tDCS group. The right-leg RM and right-leg VL elicited the greatest muscle activation during set 1 after a-tDCS and Sham, respectively (p < 0.05). Our results revealed that a-tDCS over the DLPFC might impact movement velocity or fatigue tolerance in well-trained individuals. Notwithstanding, significant differences in dominant-leg muscle activity were found both in a-tDCS and Sham.This study aimed to evaluate the effects of preceding anodal transcranial direct stimulation (a-tDCS) over the dorsolateral prefrontal cortex (DLPFC) during the back squat exercise on movement velocity and surface electromyographic (sEMG) activity. Thirteen healthy, well-trained, male firefighters (34.72 ± 3.33 years; 178 ± 7.61 cm; 76.85 ± 11.21 kg; 26.8 ± 4.2 kg·m To optimise strength training, new promising techniques such as transcranial direct current stimulation (tDCS) are available . This toOn the other hand, the control of movement velocity has lately been proposed as a valid alternative way to monitor training load when seeking training optimisation ,11. The Complementary, surface electromyography (sEMG) devices have also been used to monitor fatigue during exercise ,18. IndeWe hypothesised that the application of a-tDCS before training would result in the increase of exercise movement velocity and muscle activity in both legs during several sets of back squats (BS) at 70% of 1-RM.A total of 16 healthy male firefighters from the Royal Official Fire Brigade of Malaga were potentially eligible to participate in this research. None of the participants had previous lower-limb injuries during the six months prior to the study, had more than two years of experience in strength training, and were right-leg dominant (self-reported appearance). Besides the Physical Activity Readiness Questionnaire (PARQ), all participants were assessed by means of a physical examination and a physical activity habits questionnaire, the IPAQ . All parParticipants were instructed to avoid taking analgesics (6 h), alcohol (48 h), and caffeine (6 h), and to avoid strenuous exercise (48 h) before each session. In addition, they were informed about the general experimental procedures and risk factors related to the measurement, and the research objectives and hypotheses. All tests were performed at Eshmún Sport Clinic . The research protocol was reviewed and approved by the Ethics Committee of the EADE-University of Wales Trinity Saint David  Committee’s reference number: EADECAFYD2020-2, in accordance with the ethical guidelines of the Helsinki Declaration .A randomized, double-blinded, sham-controlled crossover study was performed to evaluate the effects of a-tDCS on muscle-strength-related variables. Sham stimulation is recommended to evaluate the efficacy of the active stimulation and placebo effects . All par−1 [−1), 2 for medium (0.70–1.15 m∙s−1), and only one for heavier loads (<0.70 m∙s−1), always focusing on the concentric phase of the exercise. The rests between sets were 3 min for light and medium loads, and 5 min for heavier loads. The best repetition at each load was considered according to the criterion of the mean propulsive velocity [The warm-up consisted of five minutes of stationary cycling  at a gentle, self-selected pace. In addition, five minutes of lower-limb joint mobilisation exercises and three 30-m running accelerations were performed. Subsequently, the participants carried out 3 sets of 5 repetitions of BS with fixed weights of 20, 30, and 40 kg. The 1-RM test was performed in a multipower device  using a progressive load test . The ini−1 . Thereafvelocity . In addivelocity .The same multipower device  used during the 1-RM test was used to perform the BS exercise. Three sets of 12 repetitions were performed by each participant with a 3-min rest period between sets [2) were used to apply a 2 mA current for a total stimulation time of 20 min (ramp-up/down time of 30 s each), as has been described before [Before exercise intervention, each participant was placed in the supine position for 10 min on the laboratory couch, a position they maintained during the a-tDCS stimulation. A pair of pads immersed in a 140 mM NaCl solution containing two electrodes , were collected from the quadriceps (rectus femoris (RF) and vastus lateralis (VL)). The SENIAM project recommendations were followed for skin preparation and electrode placement on RF and VL . The skisame leg .Signals were filtered using a fourth-order Butterworth bandpass filter with a cut-off frequency at 20–450 Hz. The signal was smoothed using a window size of 0.025-s RMS, and an overlapping of 0.0125 s between windows . Before p < 0.05. The sample size was estimated using data from previous studies in which a-tDCS was investigated for its effect on kinematic variables during resistance exercise. Based on the effect size of 0.3 for a possible difference in mean concentric velocity during exercise between the a-tDCS and Sham conditions, it was estimated that at least 10 participants were necessary, with an alpha level of 0.05 and a power (1−β) of 0.80 by G*Power .Statistical analyses were performed using SPSS v.26.0 . The results were expressed as mean ± SD. Data distribution was examined for normality using the Shapiro–Wilk test. A repeated-measures analysis of variance (ANOVA) with one between-subjects factor  and one within-subjects factor ) followed by Bonferroni post-hoc tests to investigate differences in the variables measured were performed. Additionally, to investigate possible differences between legs in muscle activity, a 3-way ANOVA, including a second within-subjects factor leg (right and left) was performed. The significance level was set to p > 0.05) for the intervention group, set, or intervention × set interaction on mean concentric velocity (MV). Hence, no significant differences were observed between a-tDCS and Sham interventions on MV in any set . Thus, a higher concentric velocity loss  and a higher EI  were observed in the a-tDCS condition when set 3 was compared to set 1. However, no significant differences were observed between a-tDCS and Sham conditions.The statistical analysis showed no significant effects , and between set 2 and 3 in the Sham condition . However, there was no condition x*set, condition x*leg, or set x*leg interaction in any of the RF EMGrms assessments. However, statistical analysis revealed a significant main effect of set for both RF and VL EMGrms (F range 6.2–8.7). Thus, significant differences between a-tDCS and Sham conditions were observed in set 1 and set 2, in which right RF showed higher EMGrms values . No significant differences between legs nor between sets were observed for any variable.The muscle activity (EMGrms) in RF and VL during the BS exercise for each set and leg are shown in This study was designed to further explore the potential ergogenic effect of a-tDCS preceding RT exercises. Considering the absence of information on the effects of a-tDCS on the movement velocity, this study aimed to evaluate the acute effects of pre-training a-tDCS over the DLPFC on exercise movement velocity and lower-limb muscle activation  during the BS exercise. The main finding of the study was the no significant differences on movement velocity between a-tDCS or Sham conditions. No significant effects for any intervention , set, or intervention x set interaction on mean concentric velocity were found. Although no significant differences were observed between a-tDCS and Sham interventions at any set, the a-tDCS group experienced higher concentric velocity loss and higher EI values when comparing set 3 to set 1, an aspect that can be of great application in certain areas such as injury rehabilitation. The depolarising neural soma and hyperpolarised apical dendrite may explain this , but we p < 0.05) after the application of a-tDCScompared to the Sham condition.Overall, the previous publications on a-tDCS haveprovided data pointing to the ergogenic effects on exercise performance inhealthy individuals. Even though the application time 15–20 min), theintensity (≈2 mA), and the predominant application areas (M1 and DLPFC) arevery standardized, there is a great heterogeneity in the applied exercisemethodology. This inconsistency in the results could also be attributed to thefact that the main physiological mechanisms involved are unknown. Thefacilitation of the primary motor cortex by increasing its output duringexercise and possibly reducing supraspinal fatigue has been suggested . The fin min, theAs in the present study, other studies have found no positive effects of a-tDCS on strength development in healthy participants , nor relp < 0.01). Similarly, Kamali et al. [It should be noted that the effect of the a-tDCS application on sEMG activity has been less studied. Our analysis of muscle activity showed a higher initial activity in the RF of the right leg  compared to the Sham group (i et al.  have repi et al. . Similari et al. .However, there are also contradictory results for neuromuscular performance changes, since no sEMG data were simultaneously collected. Several attempts have been made to demonstrate the effect in different populations, but no effect was found in a larger population . In isokMore recent studies ,39 have Our study had some limitations that should be mentioned. First, this might be considered as an exploratory study due to the low sample size; however, the calculation of statistical power helped to draw accurate conclusions in a given population. Second, there are several differences in the a-tDCS protocols used to date, and even more so with respect to the Sham stimulation , which, The application of a-tDCS over the DLPFC before exercise might not elicit positive effects on movement velocity or fatigue tolerance in strength-trained individuals. However, significant differences in right-leg muscle activity both in a-tDCS and Sham were reported. More research is needed to compare the effects of a-tDCS on strength-related variables in beginners, intermediate, or advanced participants. Since increasing the intensity of the sEMG signal is one of the priority objectives in any rehabilitation  or motor